{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T11:44:12Z","timestamp":1788263052655,"version":"build-2803163510"},"reference-count":33,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T00:00:00Z","timestamp":1755907200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 AI080581"],"award-info":[{"award-number":["R01 AI080581"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Matrix metalloproteinases (MMPs) are a major group of proteases known to regulate the turnover of the extracellular matrix (ECM). We observed that induced MMP-12 promotes eosinophilic inflammation-related epithelial cell mesenchymal transition (EMT), bronchial fibrosis, and airway obstruction in an allergen-exposed mouse model of chronic airway diseases in allergen-exposed mice and in airway-specific CC10-IL-13-overexpressed mice. Our histological analysis showed that the parabronchial and perivascular accumulation of eosinophils, fibroblasts, and collagen is significantly decreased in MMP-12\u2212\/\u2212 allergen-exposed mice and airway-specific rtTA-MMP-12\u2212\/\u2212CC-10-IL-13-overexpressed mice compared to allergen-exposed wild-type mice and rtTA-CC10-IL-13-overexpressed mice. ELISA and Western blot analyses validated these histological findings, demonstrating that EMT and profibrotic protein levels were significantly decreased in allergen-challenged MMP-12\u2212\/\u2212 mice and rtTA-MMP-12\u2212\/\u2212CC10-IL-13-overexpressed mice in comparison to the allergen-exposed wild-type mice and rtTA-CC10-IL-13-overexpressed mice. In addition, we also observed that allergen-challenged MMP-12\u2212\/\u2212 mice have improved resistance and compliance compared to allergen-challenged wild-type mice. Most importantly, we show that treatment with MMP-12 inhibitors (PF-00356231 and MMP408) restricts the induction and progression of bronchial fibrosis and airway restrictions in allergen-exposed mice and airway-specific rtTA-CC10-IL-13 mice compared to the respective control mice. Taken together, the novelty of these findings lie in the fact that induced MMP-12 regulates eosinophilic inflammation-induced bronchial fibrosis and associated airway restriction, which may be reduced by treatment with MMP-12 inhibitors.<\/jats:p>","DOI":"10.3390\/cells14171307","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:09:32Z","timestamp":1756080572000},"page":"1307","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["MMP-12 Inhibitors Inverse Eosinophilic Inflammation-Mediated Bronchial Fibrosis in Murine Models of Pulmonary Airway Obstruction"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6900-9447","authenticated-orcid":false,"given":"Chandra Sekhar","family":"Kathera","sequence":"first","affiliation":[{"name":"John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7776-1543","authenticated-orcid":false,"given":"Chandra Sekhar","family":"Yadavalli","sequence":"additional","affiliation":[{"name":"John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil","family":"Mishra","sequence":"additional","affiliation":[{"name":"John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Cabral-Pacheco, G.A., Garza-Veloz, I., Castruita-De la Rosa, C., Ramirez-Acu\u00f1a, J.M., Perez-Romero, B.A., Guerrero-Rodriguez, J.F., Martinez-Avila, N., and Martinez-Fierro, M.L. (2020). The roles of matrix metalloproteinases and their inhibitors in human diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249739"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nrm2125","article-title":"Matrix metalloproteinases and the regulation of tissue remodelling","volume":"8","author":"Ewald","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1136\/thx.2005.051979","article-title":"Matrix metalloproteinases in destructive pulmonary pathology","volume":"61","author":"Elkington","year":"2006","journal-title":"Thorax"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Christopoulou, M.-E., Papakonstantinou, E., and Stolz, D. (2023). Matrix metalloproteinases in chronic obstructive pulmonary disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043786"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.jaci.2010.05.015","article-title":"IL-13 and TH2 cytokine exposure triggers matrix metalloproteinase 7\u2013mediated Fas ligand cleavage from bronchial epithelial cells","volume":"126","author":"Wadsworth","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1513\/pats.200603-068MS","article-title":"State of the art. Mechanistic heterogeneity in chronic obstructive pulmonary disease: Insights from transgenic mice","volume":"3","author":"Elias","year":"2006","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1097\/00063198-200301000-00005","article-title":"Role of matrix metalloproteinases in asthma","volume":"9","author":"Kelly","year":"2003","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kondo, N., Temma, T., Aita, K., Shimochi, S., Koshino, K., Senda, M., and Iida, H. (2018). Development of matrix metalloproteinase-targeted probes for lung inflammation detection with positron emission tomography. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-19890-1"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Thickett, D.R., Perkins, G.D., O\u2019Kane, C., McKeown, S., and McAuley, D. (2008). Does MMP-12 play a role in human lung fibrosis?. Am. J. Respir. Cell Mol. Biol., 38.","DOI":"10.1165\/ajrcmb.38.2.247"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1172\/JCI0214136","article-title":"Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling","volume":"110","author":"Lanone","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12189","DOI":"10.1074\/jbc.272.18.12189","article-title":"Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase","volume":"272","author":"Gronski","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1172\/JCI10458","article-title":"Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema","volume":"106","author":"Zheng","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yadavalli, C.S., Upparahalli Venkateshaiah, S., Kumar, S., Kandikattu, H.K., Oruganti, L., Kathera, C.S., and Mishra, A. (2023). Allergen-induced NLRP3\/caspase1\/IL-18 signaling initiate eosinophilic esophagitis and respective inhibitors protect disease pathogenesis. Commun. Biol., 6.","DOI":"10.1038\/s42003-023-05130-4"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e202000979","DOI":"10.26508\/lsa.202000979","article-title":"Macrophages-induced IL-18\u2013mediated eosinophilia promotes characteristics of pancreatic malignancy","volume":"4","author":"Kandikattu","year":"2021","journal-title":"Life Sci. Alliance"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1111\/all.15180","article-title":"Role of IL-18-transformed CD274-expressing eosinophils in promoting airway obstruction in experimental asthma","volume":"77","author":"Mishra","year":"2022","journal-title":"Allergy"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1021\/jm900093d","article-title":"A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): Discovery of (S)-2-(8-(methoxycarbonylamino) dibenzo [b, d] furan-3-sulfonamido)-3-methylbutanoic acid (MMP408)","volume":"52","author":"Li","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Aristorena, M., Gallardo-Vara, E., Vicen, M., de Las Casas-Engel, M., Ojeda-Fernandez, L., Nieto, C., Blanco, F.J., Valbuena-Diez, A.C., Botella, L.M., and Nachtigal, P. (2019). MMP-12, secreted by pro-inflammatory macrophages, targets endoglin in human macrophages and endothelial cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20123107"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s12016-025-09045-2","article-title":"Targeting il-13 and il-4 in asthma: Therapeutic implications on airway remodeling in severe asthma","volume":"68","author":"Sahnoon","year":"2025","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_19","first-page":"805","article-title":"Molecular changes underlying pulmonary emphysema and chronic bronchitis in Chronic Obstructive Pulmonary Disease: An updated review","volume":"39","year":"2024","journal-title":"Histol. Histopathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"196","DOI":"10.5114\/aoms\/114117","article-title":"Association of the MMP-3, MMP-9 and MMP-12 gene polymorphisms with COPD risk: A meta-analysis","volume":"20","author":"Zhao","year":"2024","journal-title":"Arch. Med. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"108820","DOI":"10.1016\/j.pharmthera.2025.108820","article-title":"The role of macrophages in asthma-related fibrosis and remodelling","volume":"269","author":"Yang","year":"2025","journal-title":"Pharmacol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1164\/ajrccm.163.3.2001073","article-title":"Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema","volume":"163","author":"Imai","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_23","first-page":"1077","article-title":"Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema","volume":"78","author":"Ohnishi","year":"1998","journal-title":"Lab. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1164\/ajrccm.159.6.9809043","article-title":"Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema","volume":"159","author":"Betsuyaku","year":"1999","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.coph.2004.12.005","article-title":"Matrix metalloproteinases in asthma and COPD","volume":"5","author":"Demedts","year":"2005","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1378\/chest.117.3.684","article-title":"Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD","volume":"117","author":"Pardo","year":"2000","journal-title":"Chest"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S160","DOI":"10.1164\/ajrccm\/150.6_Pt_2.S160","article-title":"Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease","volume":"150","author":"Shapiro","year":"1994","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/1465-9921-8-81","article-title":"Patterns of airway inflammation and MMP-12 expression in smokers and ex-smokers with COPD","volume":"8","author":"Babusyte","year":"2007","journal-title":"Respir. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1056\/NEJMoa0904006","article-title":"MMP12, lung function, and COPD in high-risk populations","volume":"361","author":"Hunninghake","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.semcancer.2022.09.004","article-title":"TGF-beta in developmental and fibrogenic EMTs","volume":"86","author":"Lee","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1183\/09031936.00068712","article-title":"Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-beta1 in airway fibroblasts in asthma","volume":"43","author":"Firszt","year":"2014","journal-title":"Eur. Respir. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.4049\/jimmunol.0903008","article-title":"Matrix metalloproteinase 12-deficiency augments extracellular matrix degrading metalloproteinases and attenuates IL-13-dependent fibrosis","volume":"184","author":"Madala","year":"2010","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1165\/rcmb.2003-0051OC","article-title":"Interleukin-13-dependent expression of matrix metalloproteinase-12 is required for the development of airway eosinophilia in mice","volume":"30","author":"Pouladi","year":"2004","journal-title":"Am. J. Respir. Cell Mol. Biol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/17\/1307\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:34:55Z","timestamp":1760034895000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/17\/1307"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,23]]},"references-count":33,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["cells14171307"],"URL":"https:\/\/doi.org\/10.3390\/cells14171307","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,23]]}}}